Programmed cell death 4: A novel player in the pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a pathological condition recognized by menstrual cycle irregularities, androgen excess, and polycystic ovarian morphology, affecting a significant proportion of women of childbearing age and accounting for the most prevalent cause of anovulatory sterility. In addition, PCOS is frequently accompanied by metabolic and endocrine disturbances such as obesity, dyslipidemia, insulin resistance, and hyperinsulinemia, indicating the multiplicity of mechanisms implicated in the progression of PCOS. However, the exact pathogenesis of PCOS is yet to be elucidated. Programmed cell death 4 (PDCD4) is a ubiquitously expressed protein that contributes to the regulation of various cellular processes, including gene expression, cell cycle progression, proliferation, and apoptosis. Despite some disparities concerning its exact cellular effects, PDCD4 is generally characterized as a protein that inhibits cell cycle progression and proliferation and instead drives the cell into apoptosis. The apoptosis of granulosa cells (GCs) is speculated to take a major part in the occurrence and progression of PCOS by ceasing antral follicle development and compromising oocyte competence. Given the possible involvement of GC apoptosis in the progression of PCOS, as well as the contribution of PDCD4 to the regulation of cell apoptosis and the development of metabolic diseases, the current review aimed to discuss whether or how PDCD4 can play a role in the pathogenesis of PCOS by affecting GC apoptosis.

TGF-ß1 receptor blockade attenuates unilateral ureteral obstruction-induced renal fibrosis in C57BL/6 mice through attenuating Smad and MAPK pathways.

Renal fibrosis is characterized by accumulation of extracellular matrix components and collagen deposition. TGF-ß1 acts as a master switch promoting renal fibrosis through Smad dependent and/or Smad independent pathways. Thirty-five male C57BL/6 mice were divided into five groups of seven each; sham, unilateral ureteral obstruction (UUO), UUO+galunisertib (150 and 300 mg/kg/day), galunisertib (300 mg/kg/day). The UUO markedly induced renal fibrosis and injury as indicated by renal functional loss, increased levels of collagen Iα1, fibronectin and α-SMA; it also activated both the Smad 2/3 and MAPKs pathways as indicated by increased levels of TGF-ß1, p-Smad 2, p-Smad 3, p-p38, p-JNK and p-ERK. These UUO-induced changes were markedly attenuated by oral administration of galunisertib, the TGFßRI small molecule inhibitor. In conclusion, we demonstrated that TGF-ß1 receptor blockade can prevent UUO-induced renal fibrosis through indirect modulation of Smad and MAPKs signaling pathways and may be useful as a therapeutic agent in treatment and/or prevention of renal fibrosis.

Inhibition of USP14 induces ER stress-mediated autophagy without apoptosis in lung cancer cell line A549.

Non-small cell lung cancer is the most common type of lung cancer, accounting for more than 80% of this tumor. Ubiquitin-specific protease (USP) 14 is one of the 100 deubiquitinating enzymes that is overexpressed in lung cancer and has been validated as a therapeutic target. The aim of this study is to determine whether the accumulation of ubiquitinated proteins results in endoplasmic reticulum (ER) stress-mediated autophagy. To inhibit USP-14, A549 lung cancer cells were treated with USP-14 siRNA and IU1-47 (20 µM). The protein level, mRNA expression, and cell cycle analysis were evaluated using Western blot, real-time PCR, and flow cytometry, respectively. We found that treating A549 cells with USP14 inhibitors significantly reduced the proliferation rate and induced cell cycle arrest at G2/M phase. We also found that USP14 inhibitors did not induce apoptosis but actually induced autophagy through accumulation of ubiquitinated proteins/ER stress/unfolded protein response (UPR) axis. Moreover, we have for the first time demonstrated that the USP14 inhibition induces ER stress-mediated autophagy in A549 cells by activation of c-Jun N-terminal kinase 1 (JNK1). In conclusion, the current investigation represents a new mechanism by which inhibition of USP14 triggers autophagy via ER stress-mediated UPR in A549 cells.